Process for the preparation of cyclic imides in the presence of polyphosphoric acid

ABSTRACT

The present invention relates to a novel process for the preparation of N-substituted cyclic imides. N-substituted cyclic imides are valuable intermediates which can be employed, for example, for the synthesis of pharmacologically valuable compounds.

The present invention relates to a novel process for the preparation ofN-substituted cyclic imides. N-substituted cyclic imides are valuableintermediates which can be employed, for example, for the synthesis ofpharmacologically valuable compounds.

According to the literature, N-phenyl-substituted cyclic imides can beprepared in a 2-3-step process by reaction of anilines with the cyclicanhydrides of dicarboxylic acids. To this end, firstly, in a first step,the aniline is reacted with the cyclic dicarboxylic anhydride withcleavage of the anhydride ring to form the corresponding open-chainmonoamide and is worked up. The monoamide obtained is subsequently, in asecond step, reacted with carboxylic acid activators (via a mixedanhydride), such as N,N′-disuccinimidyl oxalate (Kometani T, Fitz T,Watt D S; Tet. Lett. 1986, 27, 919), acetic anhydride (Stiz D S, Souza MM, Golin V, Neto R A S, Correa R, Nunes R J, Yunes R A, Cechinel-FilhoV; Pharmazie 2000, 55, 12; Wanner M J, Koomen G-J; Tetrahedron 1991, 47,8431; Akula M R, Kabalka G W; Synth. Commun. 1998, 28, 2063; Shemchuk LA, Chernykh V P, Ivanova I L, Snitkovskii E L, Zhirov M V, Turov A V;Russ. J. Org. Chem. 1999, 35, 286) or thionyl chloride (Caulfield W L,Gibson S, Rae D R; J. Chem. Soc., Perkin Trans 1 1996, 545), to give thecorresponding N-substituted cyclic imides.

JP 62212361 describes the preparation of cyclic imides by reaction ofaniline and dicarboxylic anhydride in toluene at 50-160° C. in thepresence of ion exchanger resins. Under these conditions, onlyortho-diamines can be reacted in one step with glutaric anhydride togive 1-aminoarylpiperidine-2,6-diones.

Hoey G B et al. describe the reaction of aniline and o-methylanilinewith glutaric or succinic acid under pressure, distillation of theresultant water or azeotropic removal of the water formed [J. Am. Chem.Soc. 1951, 4473]. With succinic acid, in no case was a cyclic imideobtained. With glutaric acid, cyclic imide was obtained, if this productwas obtained at all, in a maximum amount of 20%.

As described, the known processes for the preparation of cyclic imidesrequire at least 2 reaction steps to be carried out and/or result inreaction mixtures, which makes work-up of the products obtained in eachcase necessary. If a one-step reaction process is described, thisresults, if the cyclic imide is obtained at all, in product mixtureswhich have to be purified. In addition, cyclic imide is only obtained inlow yields.

The object of the present invention was to provide an improved processfor the synthesis of N-substituted cyclic imides which avoids theabove-described disadvantages of the previous processes. In particular,the process should be simplified and the yield increased.

Surprisingly, it has been found that N-substituted cyclic imides can beobtained in a one-step process and in high yield if the primary amine isreacted directly with the corresponding ring-forming dicarboxylic acidin the presence of polyphosphoric acid. The present invention thereforerelates to a process for the preparation of N-substituted cyclic imideswhich is characterised in that a primary amine is reacted with adicarboxylic acid in the presence of polyphosphoric acid.

Polyphosphoric acid (PPA) is a mixture of up to 85% of phosphoruspentoxide and orthophosphoric acid and also linear polyphosphoric acid(Rowlands D A; Synth. Reagents 1985, 6, 156)

Suitable as primary amine are unbranched and branched alkylamines andarylamines, which may be unsubstituted and substituted. As arylamines,preference is given to unsubstituted and substituted aniline. Particularpreference is given to substituted or unsubstituted aniline of thegeneral formula I.

in which

-   -   R, R′, R″, independently of one another, are H, F, Cl, Br, I,        alkyl, O-alkyl, —(C═O)alkyl, O—(C═O)alkyl, aryl, COOH,        —(C═O)aryl, OCF₃, CF₃, CN, OCHF₂ or2,3-CH═CH—CH═CH—,    -   A is H, NO₂, NH₂ or NH—(C═O)—R¹,    -   alkyl is unbranched or branched alkyl having 1-6 C atoms,    -   aryl is phenyl or thienyl, each of which is unsubstituted or        monosubstituted by alkyl, O-alkyl, CF₃,    -   R¹ is 2-phenoxy-2-aryl(or alkyl)acetamide or        2-phenylamino-2-aryl(or alkyl)acetamide

Alkyl is unbranched (linear) or branched, and has 1, 2, 3, 4, 5 or 6 Catoms. Alkyl preferably denotes methyl, furthermore ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore alsopentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl,1-ethylpropyl, hexyl, 1-, 2-, 3-or 4-methylpentyl, 1,1-, 1,2-, 1,3-,2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl,1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or1,2,2-trimethylpropyl, furthermore preferably, for example,trifluoromethyl.

Alkyl is very particularly preferably methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl ortrifluoromethyl.

A can be in the ortho-, meta- or para-position (4-position) to theprimary amino group. A is preferably in the 4-position to the aminogroup. A is particularly preferably a nitro group and is in the4-position to the primary amino group.

Suitable as dicarboxylic acid are unbranched and branched alkanes oralkenes which have an aliphatic chain containing 2, 3, 4 or 5 C atomsbetween the 2 carboxyl groups and are capable of forming a cyclic imidewith the primary amine. Examples are saturated aliphatic dicarboxylicacids, such as succinic acid, glutaric acid, adipic acid, pimelic acid,but also dicarboxylic acids which contain one or more double bonds, suchas, for example, maleic acid. Preference is given to dicarboxylic acidswhich have an aliphatic chain containing 2 or 3 C atoms between the 2carboxyl groups, in particular maleic acid, succinic acid andsubstituted and unsubstituted glutaric acid. If branched glutaric acidis used, one or 2 of the H atoms in the 3-position is preferablysubstituted by alkyl having 1 to 6 C atoms or aryl.

In the reaction according to the invention of a primary amine of theformula I with one of the preferred dicarboxylic acids, the reactionproduct obtained is a cyclic imide of the general formula II

in which

-   -   R, R′, R″, independently of one another, are H, F, Cl, Br, I,        alkyl, O-alkyl, —(C═O)alkyl, O—(C═O)alkyl, aryl, COOH,        —(C═O)aryl, OCF₃, CF₃, CN, OCHF₂ or2,3-CH═CH—CH═CH—,    -   A is H, NO₂, NH₂ or NH—(C═O)—R¹,    -   x is —CH₂CH₂CH₂—, —CH₂CH₂—, —CH═CH—, —CH₂C(alkyl)₂CH₂—,        —CH₂CH(alkyl)CH₂— or —CH₂CH-aryl-CH₂—,    -   alkyl is unbranched or branched alkyl having 1-6 C atoms,    -   aryl is phenyl or thienyl, each of which is unsubstituted or        monosubstituted by alkyl, O-alkyl, CF₃,    -   R¹ is 2-phenoxy-2-aryl(or alkyl)acetamide or        2-phenylamino-2-aryl(or alkyl)acetamide.

In particular, the compounds of the formula II are valuableintermediates which can serve, for example, for the preparation ofcertain 2-phenoxy-2-aryl(or alkyl)acetamides or 2-phenylamino-2-aryl(oralkyl)acetamides, which act as inhibitors of coagulation Xa and VIIa.Compounds of this type are described, for example, in the pending Germanpatent application No. 101 02322.

The reaction scheme whence scratch that the reaction sequence isdepicted below for the particularly preferred glutaric acid (III),succinic acid (IV) and maleic acid (V) (reaction scheme 1).

The process according to the invention can be carried out in a simplemanner, preferably by bringing equimolar amounts of the two reactants toreaction with stirring in PPA at 55° C. to 95° C., particularlypreferably at about 70° C., until the reaction is complete (2 h to 24h). The reaction mixture is subsequently diluted with water, with theproduct generally precipitating cleanly in crystalline form.

Compared with the processes known hitherto, the process according to theinvention is significantly simpler to carry out and proceeds withsignificantly increased yield. Furthermore, further product purificationis generally not necessary. It is therefore to be preferred over theknown processes both from an economic and ecological point of view.

If the product obtained is an N-arylated cycloimide which contains oneor more nitro group(s) in the aryl moiety, the nitro group(s) presentcan be reduced in a simple manner to (the) amino group(s) (see step 2 ofExample 1). In this way, for example, N-(aminophenyl)cycloimidecompounds may be present which can then be converted into furthervaluable compounds.

The invention thus furthermore relates to a process for the preparationof substituted N-(aminoaryl)cycloimide compounds which is characterisedin that (a) firstly an aryl compound containing at least one nitro groupis reacted with a dicarboxylic acid in the presence of polyphosphoricacid to give the corresponding N-(nitroaryl)cycloimide compound and (b)the resultant N-(nitroaryl)cycloimide compound is subsequently reducedto the corresponding N-(aminoaryl)cycloimide compound. In this way,preferably N-(aminophenyl)cycloimide compounds, particularly preferablyN-(4-aminophenyl)cycloimide compounds, are prepared. Suitable reducingagents for the reduction of the nitro group to the amino group are, forexample, Raney nickel/hydrogen (RaNi/H₂) andpalladium-on-carbon/hydrogen (Pd—C/H₂). Preference is given to the useof Raney nickel/hydrogen. Suitable solvents for carrying out thereduction are, for example, tetrahydrofuran (THF) and/or methanol.

Mention may be made here by way of example of the preparation of1-(4-nitrophenyl)piperidine-2,6-diones,1-(4-nitrophenyl)pyrrole-2,5-diones or1-(4-nitrophenyl)pyrrolidine-2,5-diones and reduction thereof to1-(4-amino-phenyl)piperidine-2,6-diones,1-(4-aminophenyl)pyrrole-2,5-diones or1-(4-aminophenyl)pyrrolidine-2,5-diones respectively. These compoundsare valuable intermediates which can be converted further intopharmacologically active compounds, in particular into inhibitors ofcoagulation factor Xa. At this point, mention may be made by way ofexample of the conversion of 1-(4-nitrophenyl)piperidine-2,6-dione into(2-(3-carbamimidoylphenoxy)-N-[4-(2,6-dioxopiperidin-1-yl)phenyl]-2-phenylacetamide)which is described in the pending German patent application No. 101 02322.

The examples, without being restricted thereto, explain the invention.

EXAMPLE 1

Step 1: 10.0 g (0.072 mol) of 4-nitroaniline 1and 9.512 g (0.072 mol) ofglutaric acid 2 are stirred for 12 h at 80° C. in 50.0 g ofpoly-phosphoric acid. After cooling, 500 mL of water are added withstirring. The resultant precipitate is filtered off with suction, rinsedwith water and dried under reduced pressure at 60° C., giving 16.3 g(96.7%) of 1-(4-nitrophenyl)piperidine-2,6-dione 3 having a meltingpoint of 207-209° C.

¹H-NMR (DMSO-d6): 8.30 (d, J=8.8, 2H), 7.46 (d, J=8.8, 2H), 2.79 (t,J=7.9, 4H), 2.03 (m, J=7.9, 2H).

Step 2: 10.0 g (0.043 mol) of 1-(4-nitrophenyl)piperidine-2,6-dione 3are dissolved in 100 mL of tetrahydrofuran, 1.0 g of RaNi/H₂ is added,and the mixture is hydrogenated using hydrogen at atmospheric pressurewith stirring. After uptake of hydrogen has taken place, the catalyst isfiltered off, and the resultant reaction-mixture solution is evaporated.The residue is recrystallised from diethyl ether, giving 7.4 g (84.9%)of 1-(4-aminophenyl)piperidine-2,6-dione 4 having a melting point of214-215° C.

¹H-NMR (DMSO-d6): 6.67 (d, J=8.8, 2H), 6.53 (d, J=8.8, 2H), 5.11 (s-br,2H), 2.67 (t, J=7.9, 4H), 1.92 (m, J=7.9, 2H).

EXAMPLE 2

Using the correspondingly substituted aniline and glutaric acid,3,3-disubstituted glutaric acid, succinic acid or maleic acid, thefollowing compounds are prepared analogously to the process described asstep 1 in Example 1:

-   -   1-(2-methyl-4-nitrophenyl)piperidine-2,6-dione (1)    -   1-(2-chloro-4-nitrophenyl)piperidine-2,6-dione (2)    -   1-(2-methoxy-4-nitrophenyl)piperidine-2,6-dione (3)    -   1-(2-bromo-4-nitrophenyl)piperidine-2,6-dione (4)    -   1-(2,4-dinitrophenyl)piperidine-2,6-dione (5)    -   1-(2-triflouromethyl-4-nitrophenyl)piperidine-2,6-dione (6)    -   1-(3-triflouromethyl-4-nitrophenyl)piperidine-2,6-dione (7)    -   1-(2,6-dichloro-4-nitrophenyl)piperidine-2,6-dione (8)    -   1-(2-phenyl-4-nitrophenyl)piperidine-2,6-dione (9)    -   4,4-dimethyl-1-(4-nitrophenyl)piperidine-2,6-dione (10)    -   1-(3-nitrophenyl)piperidine-2,6-dione (11)    -   1-(2-nitrophenyl)piperidine-2,6-dione (12)    -   1-(4-ethylphenyl)piperidine-2,6-dione (13)    -   1-(3-chlorophenyl)piperidine-2,6-dione (14)    -   1-(4-chlorophenyl)piperidine-2,6-dione (15)    -   1-(4-nitrophenyl)pyrrolidine-2,5-dione (16)    -   1-(2-chloro-4-nitrophenyl)pyrrolidine-2,5-dione (17)    -   1-(2,4-dinitrophenyl)pyrrolidine-2,5-dione (18)    -   1-(2-methyl-4-nitrophenyl)pyrrolidine-2,5-dione (19)    -   1-(2,6-dichloro-4-nitrophenyl)pyrrolidine-2,5-dione (20)    -   1-(2-bromo-4-nitrophenyl)pyrrolidine-2,5-dione (21)    -   1-(2-benzoyl-4-nitrophenyl)pyrrolidine-2,5-dione (22)    -   1-(2-methoxy-4-nitrophenyl)pyrrolidine-2,5-dione (23)    -   1-(2-carboxy-4-nitrophenyl)pyrrolidine-2,5-dione (24)    -   1-(2-triflouromethyl-4-nitrophenyl)pyrrolidine-2,5-dione (25)    -   1-(3-triflouromethyl-4-nitrophenyl)pyrrolidine-2,5-dione (26)    -   1-(2-phenyl-4-nitrophenyl)pyrrolidine-2,5-dione (27)    -   1-(4-nitrophenyl)pyrrole-2,5-dione (28)    -   1-(2-triflouromethyl-4-nitrophenyl )pyrrole-2,5-dione (29)

EXAMPLE 3

A selection of the compounds prepared in accordance with Example 2 areconverted into the compounds mentioned below analogously to theprocesses described as step 2 in Example 1:

-   -   compound 6 into        1-(2-triflouromethyl-4-aminophenyl)piperidine-2,6-dione (30)    -   compound 3 into 1-(2-methoxy-4-aminophenyl)piperidine-2,6-dione        (31)    -   compound 1 into 1-(2-methyl-4-aminophenyl)piperidine-2,6-dione        (32)    -   compound 7 into        1-(3-triflouromethyl-4-aminophenyl)piperidine-2,6-dione (33)    -   compound 10 into        4,4-dimethyl-1-(4-aminophenyl)piperidine-2,6-dione (34)    -   compound 16 into 1-(4-aminophenyl)pyrrolidine-2,5-dione (35)    -   compound 17 into 1-(2-chloro-4-aminophenyl)pyrrolidine-2,5-dione        (36)    -   compound 18 into 1-(2,4-diaminophenyl)pyrrolidine-2,5-dione (37)    -   compound 19 into 1-(2-methyl-4-aminophenyl)pyrrolidine-2,5-dione        (38)    -   compound 20 into        1-(2,6-dichloro-4-aminophenyl)pyrrolidine-2,5-dione (39)    -   compound 23 into        1-(2-methoxy-4-aminophenyl)pyrrolidine-2,5-dione (40)    -   compound 26 into        1-(3-triflouromethyl-4-aminophenyl)pyrrolidine-2,5-dione (41)    -   compound 25 into        1-(2-triflouromethyl-4-aminophenyl)pyrrolidine-2,5-dione (42)

All compounds prepared were characterised by mass spectroscopy.Furthermore, the solid point (SP) of all compounds was determined. Theresults are shown in Table 1.

Mass spectrometry (MS): EI (electron impact ionisation) M⁺

-   -   FAB (fast atom bombardment) (M+H)⁺

Above and below, all temperatures are indicated in ° C. TABLE 1 MS MW SPEI/ No. chemical structure [g/mol]; [° C.] FAB] 1

248.24 175-179 249 2

268.66 179-182 269 3

264.24 172-177 265 4

313.11 117-120 313 5

279.21 169-170 280 6

302.21 176-177 302 7

302.21 125-126 302 8

303.10 206-207 304 9

310.31 139-140 310 10

262.27 201-202 262 11

234.21 205-206 235 12

234.21 97-98 235 13

217.27 135-136 218 14

223.66 128-129 224 15

223.66 143-144 224 16

220.19 215-217 220 17

254.63 160-162 254 18

265.18 220-222 265 19

234.21 205-207 234 20

289.08 199-201 288 21

299.08 169-171 298 22

324.30 174-176 324 23

250.21 167-169 250 24

264.20 246-250 264 25

288.19 205-207 288 26

288.19 106-107 288 27

296.29 135-137 296 28

218.17 170-171 218 29

286.17 109-111 287 30

272.23 201-202 273 31

234.26 120-121 234 32

218.26 153-154 218 33

272.23 169-170 273 34

232.29 185-186 233 35

190.20 240-242 190 36

224.65 230-232 224 37

205.22 240-242 205 38

204.23 174-175 204 39

259.09 255-257 258 40

220.23 161-163 220 41

258.20 115-117 258 42

258.20 157-159 258

1. Process for the preparation of N-substituted cyclic imides, which ischaracterised in that a primary amine is reacted with a dicarboxylicacid in the presence of polyphosphoric acid
 2. Process according toclaim 1, characterised in that the primary amine employed is substitutedor unsubstituted aniline
 3. Process according to claim 2, characterisedin that the primary amine employed is a compound of the general formulaI

in which R, R′, R″, independently of one another, are H, F, Cl, Br, I,alkyl, O-alkyl, —(C═O)alkyl, O—(C═O)alkyl, aryl, COOH, —(C═O)aryl, OCF₃,CF₃, CN, OCHF₂ or2,3-CH═CH—CH═CH—, A is H, NO₂, NH₂ or NH—(C═O)—R¹,alkyl is unbranched or branched alkyl having 1-6 C atoms, aryl is phenylor thienyl, each of which is unsubstituted or monosubstituted by alkyl,O-alkyl, CF₃, R¹ is 2-phenoxy-2-aryl(or alkyl)acetamide or2-phenylamino-2-aryl(or alkyl)acetamide
 4. Process according to claim 1,characterised in that the dicarboxylic acid employed is maleic acid,succinic acid or substituted or unsubstituted glutaric acid
 5. Processaccording to claim 1, characterised in that equimolar amounts of primaryamine and dicarboxylic acid are reacted with one another
 6. Process forthe preparation of substituted N-(aminoaryl)cycloimide compounds, whichis characterised in that (a) firstly an aryl compound containing atleast one nitro group is reacted with a dicarboxylic acid in thepresence of polyphosphoric acid to give the correspondingN-(nitroaryl)cycloimide compound and (b) the resultantN-(nitroaryl)cycloimide compound is subsequently reduced to thecorresponding N-(aminoaryl)cycloimide compound
 7. Process according toclaim 6, is characterised in that the N-(nitroaryl)cycloimide compoundreacted in step (a) is an N-(nitrophenyl)cycloimide compound
 8. Processaccording to claim 6, characterised in that the reduction of the nitrogroup in (b) is carried out using Raney nickel/hydrogen